There are 3 parts to this study. The goal of Part 1 of this clinical
research study (called "Safety Run-In") is to find the
recommended dosing schedule of PDR001 when given with Tafinlar
(dabrafenib) and Mekinist (trametinib) in patients with melanoma. The
goal of Part 2 of this study (called "Biomarker Study") is to
understand the effects of the combination of PDR001, dabrafenib, and
trametinib. Researchers also want to study the biomarkers in patients
receiving the study drugs. Biomarkers are found in the blood/tissue and
may be related to your reaction to the study drugs. The goal of Part 3
of this study (called "Randomized") is to learn if the
recommended dosing schedule of PDR001 found in Part 1 can help control
melanoma when given in combination with dabrafenib and trametinib. In
Part 3 of the study, PDR001 will be compared to a placebo. A placebo is
not a drug. It looks like the study drug but is not designed to treat
any disease or illness. It is designed to be compared with a study drug
to learn if the study drug has any real effect.

1) (Part 1): ECOG performance status </= 1
2) (Part 1): Aspartate transaminase (AST) < 2.5× ULN and Alanine
transaminase (ALT) < 2.5× ULN
3) (Part 2): ECOG performance status </= 2
4) (Part 2): A total of at least two cutaneous or subcutaneous lesions
or nodal lesions for tumor sample collection. Lesions situated in a
previously irradiated area, or an area subject to other locoregional
therapy (e.g. intralesional injections) cannot be considered for sample collection.
5) (Part 3): ECOG performance status </= 2
6) All Subjects: >/= 18 years of at the time of informed consent
7) Written informed consent must be obtained prior to any screening procedures
8) Histologically confirmed, unresectable or metastatic melanoma (stage
IIIC or IV)
9) BRAF V600 mutation positive melanoma as assessed locally, or if local
BRAF testing is unavailable, at a Novartis designated central reference laboratory
10) Measurable disease per RECIST 1.1
11) Treatment-related toxicities (except alopecia) must = Grade 1 at the
time of randomization according to CTCAE version 4.03
12) An adequate amount of tumor tissue (archived tumor tissue, or new
biopsy if archived tissue is not available) must be available at the
time of enrollment for central validation of BRAF V600 mutation and
biomarker assessments
13) Subject has adequate bone marrow and organ function as defined by
the following laboratory values without continuous supportive treatment
(such as blood transfusion, coagulation factors and/or platelet
infusion, or red/white blood cell growth factor administration) as
assessed by laboratory for eligibility: Hematological: Absolute
neutrophil count >/= 1.5 × 109/L Platelet count >/= 100 × 109/L
Hemoglobin >/= 9 g/dL
14) contd from #13: Coagulation: PT/INR and PTT </= 1.5 x ULN.
Subjects receiving anticoagulation treatment may be allowed to
participate with INR established within the therapeutic range prior to
randomization Renal: Serum creatinine < 1.5 mg/dL Hepatic: Total
bilirubin </= 1.5 x ULN except for subjects with Gilbert’s syndrome
who may only be included if the total bilirubin is </= 3.0 × ULN or
direct bilirubin </= 1.5 × ULN
15) contd. from #14: Aspartate transaminase (AST) < 2.5 × ULN, except
for subjects with liver metastasis, who are only included if the AST is
< 5 × ULN Alanine transaminase (ALT) < 2.5 × ULN, except for
subjects with liver metastasis, who are only included if the ALT is <
5 × ULN Albumin >/= 2.5 g/dL
16) Left ventricular ejection fraction (LVEF) >/=lower limit of
institutional normal (LLN) as assessed by echocardiogram (ECHO) or
multigated acquisition (MUGA) scan
17) Able to swallow and retain oral medication and must not have any
clinically significant gastrointestinal abnormalities that may alter
absorption such as malabsorption syndrome or major resection of the
stomach or bowels
18) Subjects must avoid consumption of grapefruit, Seville oranges or
products containing the juice of each during the entire study and
preferably 7 days before the first dose of study medications, due to
potential CYP3A4 interaction with the study medications. Orange juice is allowed.

Exclusion:

1) (Part 1): Any history of CNS metastases
2) (Part 2) and (Part 3): Clinically active cerebral melanoma
metastasis. Subjects with up to three cerebral metastases are eligible,
if all lesions are stable and have been definitively treated with
stereotactic radiation therapy, surgery or gamma knife therapy with no
evidence of disease progression prior to enrollment as assessed by two
consecutive assessments >/= 6 weeks apart and have not required
steroids for at least >/= 4 weeks prior to enrollment (physiological
doses of corticosteroids are allowed).
3) All Subjects: Subjects with uveal or mucosal melanoma
4) Prior systemic anti-cancer treatment (e.g., checkpoint inhibitors,
targeted therapy [e.g. BRAF and/or MEK inhibitors], chemotherapy,
biologic therapy, tumor vaccine therapy, or any systemic investigational
treatment) for unresectable or metastatic melanoma.
5) Prior loco-regional treatment with intralesional therapy (e.g.
talimogene laherparepvec) for unresectable or metastatic melanoma in the
last 6 month prior to start of study treatment.
6) Prior neoadjuvant and/or adjuvant therapy for melanoma completed less
than 6 months prior to start of study treatment (e.g., targeted therapy,
immunotherapy [e.g. interferon], biochemotherapy, tumor vaccine).
7) Radiation therapy </= 4 weeks prior to start of study treatment
(palliative radiotherapy to bone lesions allowed </= 2 weeks prior to
start of study treatment).
8) Major surgery, open biopsy, or significant traumatic injury </= 2
weeks prior to start of study treatment. Minor surgical procedures
should be completed 7 days prior to start of study treatment.
9) Active, known or suspected autoimmune disease or a documented history
of autoimmune disease, including ulcerative colitis and Crohn’s disease
(Subjects with vitiligo, type I diabetes mellitus, residual
hypothyroidism due to autoimmune condition only requiring hormone
replacement, psoriasis not requiring systemic treatment, or conditions
not expected to recur in the absence of an external trigger are
permitted to enroll).
10) Systemic chronic steroid therapy (>/= 10mg/day prednisone or
equivalent) or any immunosuppressive therapy 7 days prior to planned
date for first dose of study treatment. Topical, inhaled, nasal and
ophthalmic steroids are allowed.
11) Current pneumonitis or interstitial lung disease.
12) History of organ transplant requiring use of immunosuppressive medication.
13) Taken an investigational drug </= 28 days or </= 5 half-lives
(minimum 14 days) prior to start of study treatment, whichever is shorter.
14) History of severe hypersensitivity reactions to other monoclonal
antibodies, which in the opinion of the investigator may pose an
increased risk of serious infusion reaction.
15) Current use of a prohibited medication.
16) Malignant disease, other than that being treated in this study.
Exceptions to this exclusion include the following: malignancies that
were treated curatively and have not recurred within 2 years prior to
study treatment; completely resected basal cell and squamous cell skin
cancers and any completely resected carcinoma in situ.
17) Active infection requiring systemic antibiotic therapy within 2
weeks prior to start of study treatment.
18) Known history of testing positive for Human Immunodeficiency Virus
(HIV) infection. For Germany only: testing positive for HIV during
screening using a local test.
19) Subjects with active Hepatitis B infection (HbsAg positive) will be
excluded. Note: Subjects with antecedent of Hepatitis B (anti-HBc
positive, HbsAg and HBV-DNA negative) are eligible.
20) Subjects with positive test for hepatitis C ribonucleic acid (HCV
RNA) Note: Subjects in whom HCV infection resolved spontaneously
(positive HCV antibodies without detectable HCV-RNA) or those that
achieved a sustained virological response after antiviral treatment and
show absence of detectable HCV RNA >/= 6 months (with the use of
IFN-free regimes) or >/= 12 months (with the use of IFN-based
regimes) after cessation of antiviral treatment are eligible
21) Any medical condition that would, in the investigator’s judgment,
prevent the subject’s participation in the clinical study due to safety
concerns, compliance with clinical study procedures or interpretation of
study results.
22) Use of any live vaccines against infectious diseases within 4 weeks
of initiation of study treatment.
23) Uncorrectable electrolyte abnormalities (e.g. hypokalemia,
hypomagnesemia, hypocalcemia), long QT syndrome or taking medicinal
products known to prolong the QT interval.
24) Known immediate or delayed hypersensitivity reaction or idiosyncrasy
to drugs chemically related to the study treatments, their excipients,
and/or dimethyl sulfoxide (DMSO).
25) Pregnant or nursing (lactating) women confirmed by a positive hCG
laboratory test within 72 hours prior to initiating study treatment.
Note: Low levels of hCG may also be considered a tumor marker, therefore
if low hCG levels are detected, another blood sample at least 4 days
later must be taken to assess the kinetics of the increase and
transvaginal ultrasound must be performed to rule out pregnancy.
26) A history or current evidence/risk of retinal vein occlusion (RVO)
or central serous retinopathy including: a) Presence of predisposing
factors to RVO or central serous retinopathy (e.g., uncontrolled
glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled
diabetes mellitus, or a history of hyperviscosity or hypercoagulability
syndromes); or b) Visible retinal pathology as assessed by ophthalmic
examination that is considered a risk factor for RVO or central serous
retinopathy such as: 1) Evidence of new optic disc cupping; 2) Evidence
of new visual field defects on automated perimetry; 3) Intraocular
pressure >21 mmHg as measured by tonometry.
27) Cardiac or cardiac repolarization abnormality, including any of the
following: ? History or current diagnosis of cardiac disease indicating
significant risk of safety for subjects participating in the study such
as uncontrolled or significant cardiac disease, including any of the
following: ? Recent (within last 6 months) myocardial infarction (MI) ?
Unstable angina (within last 6 months), ? Uncontrolled congestive heart
failure (CHF) ? Clinically significant (symptomatic) cardiac arrhythmias
(e.g., sustained ventricular tachycardia, and clinically significant
second or third degree atrioventricular [AV] block without a pacemaker).
28) Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception during dosing and for 150-days
after stopping treatment with PDR001. Highly effective contraception
methods include: a. Total abstinence (when this is in line with the
preferred and usual lifestyle of the subject). Periodic abstinence
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception. b. Female
sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks
before taking study treatment. In case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up
hormone level assessment. c. Male sterilization (at least 6 months prior
to screening).
....
Criteria truncated, please contact Prinicipal Investigator's office for
full criteria